Huffmanholdt6369

Congenital heart disease (CHD), the leading birth defect worldwide, has a largely unknown etiology, likely to result from complex interactions between genetic and environmental factors during heart development, at a time when the heart adapts to diverse physiological and pathophysiological conditions. Crucial among these is the regulation of cardiomyocyte development and postnatal maturation, governed by dynamic changes in DNA methylation. Previous work from our laboratory has shown that exposure to the environmental toxicant tetrachlorodibenzo-p-dioxin (TCDD) disrupts several molecular networks responsible for heart development and function. To test the hypothesis that the disruption caused by TCDD in the heart results from changes in DNA methylation and gene expression patterns of cardiomyocytes, we established a stable mouse embryonic stem cell line expressing a puromycin resistance selectable marker under control of the cardiomyocyte-specific Nkx2-5 promoter. Differentiation of these cells in the presence of puromycin induces the expression of a large suite of cardiomyocyte-specific markers. To assess the consequences of TCDD treatment on gene expression and DNA methylation in these cardiomyocytes, we subjected them to transcriptome and methylome analyses in the presence of TCDD. Unlike control cardiomyocytes maintained in vehicle, the TCDD-treated cardiomyocytes showed extensive gene expression changes, with a significant correlation between differential RNA expression and DNA methylation in 111 genes, many of which are key elements of pathways that regulate cardiovascular development and function. Our findings provide an important clue toward the elucidation of the complex interactions between genetic and epigenetic mechanisms after developmental TCDD exposure that may contribute to CHD.S-nitrosylation, the post-translational modification of cysteines by nitric oxide, has been implicated in several cellular processes and tissue homeostasis. As a result, alterations in the mechanisms controlling the levels of S-nitrosylated proteins have been found in pathological states. In the last few years, a role in cancer has been proposed, supported by the evidence that various oncoproteins undergo gain- or loss-of-function modifications upon S-nitrosylation. Here, we aim at providing insight into the current knowledge about the role of S-nitrosylation in different aspects of cancer biology and report the main anticancer strategies based on (i) reducing S-nitrosylation-mediated oncogenic effects, (ii) boosting S-nitrosylation to stimulate cell death, (iii) exploiting S-nitrosylation through synthetic lethality.Epstein-Barr virus (EBV)-associated T- and natural killer (NK)-cell malignancies, such as extranodal NK-/T-cell lymphoma (ENKTL), exhibit high chemoresistance and, accordingly, such patients have a poor prognosis. The rare nature of such cancers and nonmalignant T/NK lymphoproliferative disorders, such as chronic active EBV (CAEBV), has limited our understanding of the pathogenesis of these diseases. Here, we characterize a panel of ENKTL- and CAEBV-derived cell lines that had been established from human tumors to be used as preclinical models of these diseases. These cell lines were interleukin-2 dependent and found to carry EBV in a latency II gene-expression pattern. click here All cell lines demonstrated resistance to cell death induction by DNA damage-inducing agents, the current standard of care for patients with these malignancies. This resistance was not correlated with the function of the multidrug efflux pump, P-glycoprotein. However, apoptotic cell death could be consistently induced following treatment with A-1331852, a BH3-mimetic drug that specifically inhibits the prosurvival protein BCL-XL. A-1331852-induced apoptosis was most efficacious when prosurvival MCL-1 was additionally targeted, either by BH3-mimetics or genetic deletion. Xenograft models established from the ENKTL cell line SNK6 provided evidence that A-1331852 treatment could be therapeutically beneficial in vivo. The data here suggest that therapeutic targeting of BCL-XL would be effective for patients with EBV-driven T/NK proliferative diseases, however, MCL-1 could be a potential resistance factor.The therapy of advanced mycosis fungoides (MF) presents a therapeutic challenge, and the search for new therapeutic targets is ongoing. Poly(ADP-ribose) polymerase 1 was shown to be upregulated in patients with advanced MF and could be druggable by a new class of chemotherapeutic agents, PARP-1 inhibitors, which are already in clinical trials for other malignancies; however, the role of PARP-1 inhibitors in MF has never been established. We examined the efficacy of talazoparib in the murine model of cutaneous T-cell lymphoma. The cytotoxic effect of talazoparib on Moloney MuLV-induced T-cell lymphoma (MBL2) cells was a result of G2/M cell cycle arrest via the upregulation of p53. The in vivo experiments confirmed the clinical impact of talazoparib on MF tumors. When talazoparib was combined with the histone deacetylase (HDAC) inhibitor, romidepsin, the cytotoxic effect was synergized via downregulation of the DNA-repair genes Fanconianemia complementation group A (FANCA), Fanconi anemia complementation group D2 (FANCD2), and DNA topoisomerase II binding protein 1(TOPBP1)and stimulation of apoptosis via Blimp-1 (PRDM1)/Bax axis. Romidepsin increased the expression of IRF8 and Bcl-6, leading to upregulation of Blimp1and Bax; whereas talazoparib upregulated Blimp-1 and Bax via upregulation of interferon regulatory factor 4 (IRF4), leading to cleavage of caspases 6 and 7. Thus, a combination of talazoparib with romidepsin demonstrated the synergistic antilymphoma effect and warranted further investigation in a clinical trial.

Prior comparisons of brain arteriovenous malformations (AVMs) treated using stereotactic radiosurgery (SRS) with or without embolization were inherently flawed, due to differences in the pretreatment nidus volumes.

To compare the outcomes of embolization and SRS, vs SRS alone for AVMs using pre-embolization malformation features.

We retrospectively reviewed International Radiosurgery Research Foundation AVM databases from 1987 to 2018. Patients were categorized into the embolization and SRS (E+SRS) or SRS alone (SRS-only) cohorts. The 2 cohorts were matched in a 11 ratio using propensity scores. Primary outcome was defined as AVM obliteration. Secondary outcomes were post-SRS hemorrhage, all-cause mortality, radiologic and symptomatic radiation-induced changes (RIC), and cyst formation.

The matched cohorts each comprised 101 patients. Crude AVM obliteration rates were similar between the matched E+SRS vs SRS-only cohorts (48.5%vs 54.5%; odds ratio=0.788, P=.399). Cumulative probabilities of obliteration at 3, 4, 5, and 6 yr were also similar between the E+SRS (33.